Cancer continues to be a major global health burden. Despite progress in the treatment of cancer, there continues to be an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancers that are resistant to existing therapeutics.
The immune system is capable of identifying tumor-associated antigens and eliminating the cancerous cells expressing them. This process of tumor immune surveillance, or tumor immunoediting, plays an important role in preventing and combating the growth of tumors, and levels of tumor-infiltrating lymphocytes, and more specifically cytotoxic T cells, have been correlated to improved prognosis in a number of cancers. Thus, enhancing the immune response may provide a means to control tumors.
B7-H1 (also known as programmed death ligand 1 (PD-L1) or CD274) is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. In normal tissue, B7-H1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, as well as various nonhematopoietic cells. Its normal function is to regulate the balance between T-cell activation and tolerance through interaction with its two receptors: programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1).
B7-H1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. B7-H1 is expressed in a broad range of cancers with a high frequency. In some cancers, expression of B7-H1 has been associated with reduced survival and unfavorable prognosis. Antibodies that block the interaction between B7-H1 and its receptors are able to relieve B7-H1-dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T cells in vitro.
MEDI4736 is a human monoclonal antibody directed against human B7-H1 that is capable of blocking the binding of B7-H1 to both the PD-1 and CD80 receptors. Thus, given the high unmet need of treating tumors, including those with a high incidence rate as well as less common types with limited treatment options and poor outcomes, the effect of MEDI4736 on tumors in human patients was examined.